Dipeptidyl peptidase I (DPPI; EC 3.4.14.1) also known as cathepsin C is a lysosomal cysteine peptidase belonging to the papain family. The enzyme is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen. The cDNAs encoding rat, human and murine DPPI have been cloned and sequenced and it has been shown that the enzyme is highly conserved. DPPI is synthesized as an inactive precursor (Zymogen), and is activated by a non-autocatalytic excision of an internal activation peptide within the N-terminal propeptide. DPPI is the only member of the papain family that is functional as a tetramer, consisting of four identical subunits. Each is composed of an N-terminal fragment (the residual propart), a heavy chain and a light chain. Once activated, DPPI catalyzes the removal of dipeptides from the N-terminal end of polypeptide substrates with broad specificity. The pH optimum lies in the region of pH 5-7 using human DPPI. Recent data suggests that, beside of being an important enzyme in lysosomal protein degradation, DPPI also functions as a key enzyme in the activation of granule serine peptidases in neutrophils (cathepsin G, proteinase 3, neutrophil serine protease 4 and elastase), mast cells (chymase and tryptase) and cytotoxic T lymphocytes and natural killer cells (granzymes A and B).
Mast cells are found in many tissues, but are present in greater numbers along the epithelial linings of the body, such as the skin, respiratory tract and gastrointestinal tract. Mast cells are also located in the perivascular tissue surrounding small blood vessels. In humans, two types of mast cells have been identified; the T-type, which expresses only tryptase, and the MC-type, which expresses both tryptase and chymase. In humans, the T-type mast cells are located primarily in alveolar tissue and intestinal mucose while the TC-type cells predominate in skin and conjuctiva. Mast cells can release a range of potent inflammatory mediators including cytokines, leukotrienes, prostaglandins, histamine and proteoglycans, but among the most abundant products of mast cell activation are the serine peptidases of the chymotrypsin family; tryptase and chymase. These peptidases are situated in the mast cell lysosomes as fully active enzymes. The exact site of tryptase and chymase activation from zymogen precursors is not known, but the Golgi apparatus might play a role in that regard. DPPI, which is particular abundant in mast cells, seems to be the key enzyme responsible for activation of chymase and tryptase. Moreover, tryptase and chymase are emerging as important mediators of allergic diseases such as asthma, inflammatory bowel disease and psoriasis. After secretion from activated mast cells, there is evidence that these peptidases are heavily involved in processes of inflammation, tissue remodelling, bronchoconstriction and mucus secretion, which have made these peptidases attractive for therapeutic intervention.
Neutrophils cause considerable damage in a number of pathological conditions. When activated, neutrophils secrete destructive granular enzymes including elastase, proteinase 3 and cathepsin G and undergo oxidative bursts to release reactive oxygen intermediates. Numerous studies have been conducted on each of these activating agents in isolation. Pulmonary emphysema, COPD, cystic fibrosis, idiopathic pulmonary fibrosis, alpha-1 antitrypsin deficiency, psoriasis, sepsis and rheumatoid arthritis are just some examples of pathological conditions associated with the potent enzymes elastase, proteinase 3 and cathepsin G.
The strong evidence associating tryptase, chymase, elastase, cathepsin G and other similar inflammatory peptidases with inflammatory diseases, points out DPPI as an attractive target enzyme for therapeutic intervention against the above mentioned diseases and other similar inflammatory diseases, due to its central role in activating these peptidases (Adkison et al. 2002, J. Clin. Invest, 109, 363-271; Pham. et al. 2004, J. Immunol, 173,7277-7281).
WO2012130299 and WO2012119941 to PROZYMEX disclose nitrile compounds and use thereof as dipeptidyl peptidase inhibitors. WO 2009074829A1 to Astrazeneca also discloses peptidyl nitriles and use thereof as dipeptidyl peptidase inhibitors. WO 2010128324A1, WO154677A1 and WO 2010142985A1 to Astrazeneca discloses further nitrile compounds and use thereof as dipeptidyl peptidase inhibitors WO2013041497A1 to Boehringer Ingelheim International GMBH discloses nitrile compounds as dipeptidyl peptidase inhibitors. Nathalie Méthot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival: In Vivo Inhibition of Serine protease Processing Requires a High Fractional Inhibition of Cathepsin C, Mol Pharmacol 73:1857-1865, 2008 disclose dipeptide nitrile cathepsin C inhibitors. Nathalie Méthot, Joel Rubin, Daniel Guay, Christian Beaulieu, Diane Ethier T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival: Inhibition of the Activation of Multiple Serine proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme Processing J. Biol. Chem., Vol. 282, Issue 29, 20836-20846, Jul. 20, 2007 disclose dipeptide nitrile cathepsin C inhibitors. Jon Bondebjerg, Henrik Fuglsang, Kirsten Rosendal Valeur, John Pedersen and Lars Nærum, Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors, Bioorganic & Medicinal Chemistry Letters 16 (2006) 3614-3617 disclose compounds having a dipeptide nitrile scaffold as inhibitors of human dipeptidyl peptidase I.